Alkylsulfanyl-1,2,4-triazoles, a New Class of Allosteric Valosine Containing Protein Inhibitors. Synthesis and Structure–Activity Relationships

Abstract

Valosine containing protein (VCP), also known as p97, is a member of AAA ATPase family that is involved in several biological processes and plays a central role in the ubiquitin-mediated degradation of misfolded proteins. VCP is an ubiquitously expressed, highly abundant protein and has been found overexpressed in many tumor types, sometimes associated with poor prognosis. In this respect, VCP has recently received a great deal of attention as a potential new target for cancer therapy. In this paper, the discovery and structure-activity relationships of alkylsulfanyl-1,2,4-triazoles, a new class of potent, allosteric VCP inhibitors, are described. Medicinal chemistry manipulation of compound 1, identified via HTS, led to the discovery of potent and selective inhibitors with submicromolar activity in cells and clear mechanism of action at consistent doses. This represents a first step toward a new class of potential anticancer agents.

Degradation of the Deubiquitinating Enzyme USP33 Is Mediated by p97 and the Ubiquitin Ligase HERC2

“…For these experiments, shRNA against p97 is not ideal, because long term knockdown of p97 results in higher starting levels of USP33. We therefore used the recently described p97 inhibitor NMS-873 (33,34), which causes acute inhibition of p97 activity and circumvents potential secondary effects that may result from long term p97 depletion. Upon addition of cycloheximide to inhibit new protein synthesis, USP33 degradation was monitored.…”

A Fragment-Based Ligand Screen Against Part of a Large Protein Machine: The ND1 Domains of the AAA+ ATPase p97/VCP

“…Table S3), indicating they may bind preferentially to the N-domain ( Table 1; type III binders). Indeed, in a separate study, we identified similar fragments that bound in a cleft immediately adjacent to the adaptor-binding site in a 2D 15 bound more strongly to the ND1 protein than to the N-domain alone (Suppl . Table S3), and thus the higher affinity of the two sites is likely located in the D1 domain ( Table 1; D1 binders).…”

“…All 1D STD NMR spectra 18 were acquired on a Bruker AVANCE DRX500 MHz spectrometer at 296.8 K (referenced to 4% CH 3 OH-CH 3 OD using a coefficient of 1.0183) with a 5 mm Bruker QCI Cryoprobe ( 1 H, 13 C, 15 N, and 31 P) with actively shielded Z-gradients and a BACS-60 automated sample changer (Bruker Biospin, Billerica, MA). Samples (500 µL) containing 500 µM fragment (or less if the compound had limited solubility) and 50 µM unlabeled ND1 protein were prepared in Norell XR-55 glass NMR tubes (Norell, Marion, NC) in 100% D 2 O PBS (pH 7.5), 1 mM NaN 3 , and 1 mM DTT, 0.5% d 6 -DMSO (Norell, Marion, NC).…”

Modulation pharmacologique de la réponse au stress du réticulum endoplasmique

“…Les causes de la mort cellulaire induite par le Bortezomib sont encore incomplètement comprises, mais pourraient impliquer plusieurs voies, dont celle du stress du RE [17]. L'ATPase AAA+ p97/VCP, qui est nécessaire à la rétro-translocation des substrats de l'ERAD, peut être inhibée par l'Eeyarestatine, un inhibiteur de première génération, ou des inhibiteurs réversibles récemment identifiés tels que les quinazolines comme le DBEQ, ML240, Ml241, dont l'efficacité et la spécificité d'action sur p97/VCP sont plus importantes que sur d'autres ATPases [18,19]. Le DBeQ bloque également l'autophagie, expliquant probablement la puissance accrue de ces composés comme agents antitumoraux par rapport aux inhibiteurs du protéasome.…”